Assessing the effects of therapeutic combinations on SARS-CoV-2 infected patient outcomes: A big data approach.

BACKGROUND: The COVID-19 pandemic has demonstrated the need for efficient and comprehensive, simultaneous assessment of multiple combined novel therapies for viral infection across the range of illness severity. Randomized Controlled Trials (RCT) are the gold standard by which efficacy of therapeutic agents is demonstrated. However, they rarely are designed to assess treatment combinations across all relevant subgroups. A big data approach to analyzing real-world impacts of therapies may confirm or supplement RCT evidence to further assess effectiveness of therapeutic options for rapidly evolving diseases such as COVID-19. METHODS: Gradient Boosted Decision Tree, Deep and Convolutional Neural Network classifiers were implemented and trained on the National COVID Cohort Collaborative (N3C) data repository to predict the patients' outcome of death or discharge. Models leveraged the patients' characteristics, the severity of COVID-19 at diagnosis, and the calculated proportion of days on different treatment combinations after diagnosis as features to predict the outcome. Then, the most accurate model is utilized by eXplainable Artificial Intelligence (XAI) algorithms to provide insights about the learned treatment combination impacts on the model's final outcome prediction. RESULTS: Gradient Boosted Decision Tree classifiers present the highest prediction accuracy in identifying patient outcomes with area under the receiver operator characteristic curve of 0.90 and accuracy of 0.81 for the outcomes of death or sufficient improvement to be discharged. The resulting model predicts the treatment combinations of anticoagulants and steroids are associated with the highest probability of improvement, followed by combined anticoagulants and targeted antivirals. In contrast, monotherapies of single drugs, including use of anticoagulants without steroid or antivirals are associated with poorer outcomes. CONCLUSIONS: This machine learning model by accurately predicting the mortality provides insights about the treatment combinations associated with clinical improvement in COVID-19 patients. Analysis of the model's components suggests benefit to treatment with combination of steroids, antivirals, and anticoagulant medication. The approach also provides a framework for simultaneously evaluating multiple real-world therapeutic combinations in future research studies.

Higher hospitalization and mortality rates among SARS-CoV-2-infected persons in rural America.

PURPOSE: Rural communities are among the most underserved and resource-scarce populations in the United States. However, there are limited data on COVID-19 outcomes in rural America. This study aims to compare hospitalization rates and inpatient mortality among SARS-CoV-2-infected persons stratified by residential rurality. METHODS: This retrospective cohort study from the National COVID Cohort Collaborative (N3C) assesses 1,033,229 patients from 44 US hospital systems diagnosed with SARS-CoV-2 infection between January 2020 and June 2021. Primary outcomes were hospitalization and all-cause inpatient mortality. Secondary outcomes were utilization of supplemental oxygen, invasive mechanical ventilation, vasopressor support, extracorporeal membrane oxygenation, and incidence of major adverse cardiovascular events or hospital readmission. The analytic approach estimates 90-day survival in hospitalized patients and associations between rurality, hospitalization, and inpatient adverse events while controlling for major risk factors using Kaplan-Meier survival estimates and mixed-effects logistic regression. FINDINGS: Of 1,033,229 diagnosed COVID-19 patients included, 186,882 required hospitalization. After adjusting for demographic differences and comorbidities, urban-adjacent and nonurban-adjacent rural dwellers with COVID-19 were more likely to be hospitalized (adjusted odds ratio [aOR] 1.18, 95% confidence interval [CI], 1.16-1.21 and aOR 1.29, CI 1.24-1.1.34) and to die or be transferred to hospice (aOR 1.36, CI 1.29-1.43 and 1.37, CI 1.26-1.50), respectively. All secondary outcomes were more likely among rural patients. CONCLUSIONS: Hospitalization, inpatient mortality, and other adverse outcomes are higher among rural persons with COVID-19, even after adjusting for demographic differences and comorbidities. Further research is needed to understand the factors that drive health disparities in rural populations.

Novel Strategies to Increase COVID-19 Testing Among Underserved and Vulnerable Populations in West Virginia.

This project addressed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing barriers in rural West Virginia by providing testing enhancements that included (1) a flexible testing staff, (2) mobile testing, (3) essential supplies, and (4) specialized testing in communities of color. A total of 142 775 polymerase chain reaction tests were performed from December 2021 through February 2022; positivity rates were 21% and 17% in clinics and mobile testing venues, respectively. The project results showed that, within a statewide network of health care clinics, administrators quickly identified and distributed enhancements and thus reduced testing barriers. (Am J Public Health. 2022;112(S9):S892-S895. https://doi.org/10.2105/AJPH.2022.307004).

Community risks for SARS-CoV-2 infection among fully vaccinated US adults by rurality: A retrospective cohort study from the National COVID Cohort Collaborative.

BACKGROUND: While COVID-19 vaccines reduce adverse outcomes, post-vaccination SARS-CoV-2 infection remains problematic. We sought to identify community factors impacting risk for breakthrough infections (BTI) among fully vaccinated persons by rurality. METHODS: We conducted a retrospective cohort study of US adults sampled between January 1 and December 20, 2021, from the National COVID Cohort Collaborative (N3C). Using Kaplan-Meier and Cox-Proportional Hazards models adjusted for demographic differences and comorbid conditions, we assessed impact of rurality, county vaccine hesitancy, and county vaccination rates on risk of BTI over 180 days following two mRNA COVID-19 vaccinations between January 1 and September 21, 2021. Additionally, Cox Proportional Hazards models assessed the risk of infection among adults without documented vaccinations. We secondarily assessed the odds of hospitalization and adverse COVID-19 events based on vaccination status using multivariable logistic regression during the study period. RESULTS: Our study population included 566,128 vaccinated and 1,724,546 adults without documented vaccination. Among vaccinated persons, rurality was associated with an increased risk of BTI (adjusted hazard ratio [aHR] 1.53, 95% confidence interval [CI] 1.42-1.64, for urban-adjacent rural and 1.65, 1.42-1.91, for nonurban-adjacent rural) compared to urban dwellers. Compared to low vaccine-hesitant counties, higher risks of BTI were associated with medium (1.07, 1.02-1.12) and high (1.33, 1.23-1.43) vaccine-hesitant counties. Compared to counties with high vaccination rates, a higher risk of BTI was associated with dwelling in counties with low vaccination rates (1.34, 1.27-1.43) but not medium vaccination rates (1.00, 0.95-1.07). Community factors were also associated with higher odds of SARS-CoV-2 infection among persons without a documented vaccination. Vaccinated persons with SARS-CoV-2 infection during the study period had significantly lower odds of hospitalization and adverse events across all geographic areas and community exposures. CONCLUSIONS: Our findings suggest that community factors are associated with an increased risk of BTI, particularly in rural areas and counties with high vaccine hesitancy. Communities, such as those in rural and disproportionately vaccine hesitant areas, and certain groups at high risk for adverse breakthrough events, including immunosuppressed/compromised persons, should continue to receive public health focus, targeted interventions, and consistent guidance to help manage community spread as vaccination protection wanes.

An ordinal severity scale for COVID-19 retrospective studies using Electronic Health Record data.

Objectives: Although the World Health Organization (WHO) Clinical Progression Scale for COVID-19 is useful in prospective clinical trials, it cannot be effectively used with retrospective Electronic Health Record (EHR) datasets. Modifying the existing WHO Clinical Progression Scale, we developed an ordinal severity scale (OS) and assessed its usefulness in the analyses of COVID-19 patient outcomes using retrospective EHR data. Materials and Methods: An OS was developed to assign COVID-19 disease severity using the Observational Medical Outcomes Partnership common data model within the National COVID Cohort Collaborative (N3C) data enclave. We then evaluated usefulness of the developed OS using heterogenous EHR data from January 2020 to October 2021 submitted to N3C by 63 healthcare organizations across the United States. Principal component analysis (PCA) was employed to characterize changes in disease severity among patients during the 28-day period following COVID-19 diagnosis. Results: The data set used in this analysis consists of 2 880 456 patients. PCA of the day-to-day variation in OS levels over the totality of the 28-day period revealed contrasting patterns of variation in disease severity within the first and second 14 days and illustrated the importance of evaluation over the full 28-day period. Discussion: An OS with well-defined, robust features, based on discrete EHR data elements, is useful for assessments of COVID-19 patient outcomes, providing insights on the progression of COVID-19 disease severity over time. Conclusions: The OS provides a framework that can facilitate better understanding of the course of acute COVID-19, informing clinical decision-making and resource allocation.

Association of Vitamin D Prescribing and Clinical Outcomes in Adults Hospitalized with COVID-19.

It is unclear whether vitamin D benefits inpatients with COVID-19. Objective: To examine the relationship between vitamin D and COVID-19 outcomes. Design: Cohort study. Setting: National COVID Cohort Collaborative (N3C) database. Patients: 158,835 patients with confirmed COVID-19 and a sub-cohort with severe disease (n = 81,381) hospitalized between 1 January 2020 and 31 July 2021. Methods: We identified vitamin D prescribing using codes for vitamin D and its derivatives. We created a sub-cohort defined as having severe disease as those who required mechanical ventilation or extracorporeal membrane oxygenation (ECMO), had hospitalization >5 days, or hospitalization ending in death or hospice. Using logistic regression, we adjusted for age, sex, race, BMI, Charlson Comorbidity Index, and urban/rural residence, time period, and study site. Outcomes of interest were death or transfer to hospice, longer length of stay, and mechanical ventilation/ECMO. Results: Patients treated with vitamin D were older, had more comorbidities, and higher BMI compared with patients who did not receive vitamin D. Vitamin D treatment was associated with an increased odds of death or referral for hospice (adjusted odds ratio (AOR) 1.10: 95% CI 1.05-1.14), hospital stay >5 days (AOR 1.78: 95% CI 1.74-1.83), and increased odds of mechanical ventilation/ECMO (AOR 1.49: 95% CI 1.44-1.55). In the sub-cohort of severe COVID-19, vitamin D decreased the odds of death or hospice (AOR 0.90, 95% CI 0.86-0.94), but increased the odds of hospital stay longer >5 days (AOR 2.03, 95% CI 1.87-2.21) and mechanical ventilation/ECMO (AOR 1.16, 95% CI 1.12-1.21). Limitations: Our findings could reflect more aggressive treatment due to higher severity. Conclusion: Vitamin D treatment was associated with greater odds of extended hospitalization, mechanical ventilation/ECMO, and death or hospice referral.

An Ordinal Severity Scale for COVID-19 Retrospective Studies Using Electronic Health Record Data

Lay Summary Electronic Health Record (EHR) data collected during routine clinical care offer real world evidence to support decision making and observational research. In the wake of the COVID-19 pandemic, one of the most powerful tools used in clinical trials is the World Health Organization Clinical Progression Scale which provides a minimal set of common outcome measures for guiding research. We developed a generalizable disease severity framework to facilitate research studies utilizing EHR data. EHR data on 2,880,456 SARS-CoV-2-infected patients from 63 health centers across the United States were examined using the National COVID Cohort Collaborative (N3C). We identified and validated concept sets using standard medical terminologies necessary to assign a level of disease severity to each patient. Patterns of change in disease severity among patients during the 28-day period following a COVID-19 diagnosis were characterized and usefulness of the proposed scale was demonstrated. Our severity scale can be used in other COVID-19 observational studies and potentially future diseases requiring point-in-time monitoring of real-world data. Objectives Although the World Health Organization (WHO) Clinical Progression Scale for COVID-19 is useful in prospective clinical trials, it cannot be effectively used with retrospective Electronic Health Record (EHR) datasets. Modifying the existing WHO Clinical Progression Scale, we developed an ordinal severity scale (OS) and assessed its usefulness in the analyses of COVID-19 patient outcomes using retrospective EHR data. Methods An OS was developed to assign COVID-19 disease severity using the Observational Medical Outcomes Partnership common data model within the National COVID Cohort Collaborative (N3C) data enclave. We then evaluated usefulness of the developed OS using heterogenous EHR data from January 2020 to October 2021 submitted to N3C by 63 healthcare organizations across the United States. Principal Components Analysis (PCA) was employed to characterize changes in disease severity among patients during the 28-day period following COVID-19 diagnosis. Results The data set used in this analysis consists of 2,880,456 patients. PCA of the day-to-day variation in OS levels over the totality of the 28-day period revealed contrasting patterns of variation in disease severity within the first and second 14 days and illustrated the importance of evaluation over the full 28-day period. Discussion An OS with well-defined, robust features, based on discrete EHR data elements, is useful for assessments of COVID-19 patient outcomes, providing insights on progression of COVID-19 disease severity over time. Conclusion The OS provides a framework which can facilitate better understanding of the course of acute COVID-19, informing clinical decision-making and resource allocation.

Vitamin D Supplementation and Covid 19: Results from the U.S. N3C Data Enclave

Background It is estimated that 18% of adults in the U.S. take Vitamin D supplements. Some observational studies suggest that vitamin D supplementation activates the innate immune system and reduces the incidence and severity of viral infections. During the SARS-CoV-2 pandemic, vitamin D supplements were touted as a potential therapy to prevent the disease and/or complications. However, supportive evidence is lacking. Methods The National COVID Cohort Collaborative (N3C) enclave is the largest COVID-19 data base with nearly 1.4 million positive patients at 56 sites in the U.S. We performed a retrospective analysis of vitamin D supplementation, either prescribed before or during hospitalization for SARS-CoV-2. Results 137,399 people took vitamin D supplements out of 1.4 million. Females prescribed vitamin D outnumbered males by almost 2:1, whereas in non-users there were no sex differences. Most supplement users were older than 50. African Americans constituted 13% of the non-users, but 23% of those prescribed vitamin D. Infected individuals with any vitamin D supplementation, pre-Covid, post-Covid or both, had a 6.66% mortality rate vs 2% mortality in non-users. Similarly, nearly a third of the supplement users were hospitalized compared to 11% in the non-users. The Charlson Co-Morbidity Index was 3.0±3 (SD) in users vs 1.0±2 (SD) in non-users. Conclusion 10% of SARS-CoV-2 infected patients were taking vitamin D. They tended to be older, more likely to be African American and have significant co-morbidities. Hospitalization and mortality were higher among those taking Vitamin D in this cohort. Vitamin D is widely used to prevent and treat SARS-CoV-2 but without evidence of efficacy. Disclosures Sally L. Hodder, M.D., Gilead (Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Viiv Healthcare (Grant/Research Support, Advisor or Review Panel member)

Predicting increases in COVID-19 incidence to identify locations for targeted testing in West Virginia: A machine learning enhanced approach.

During the COVID-19 pandemic, West Virginia developed an aggressive SARS-CoV-2 testing strategy which included utilizing pop-up mobile testing in locations anticipated to have near-term increases in SARS-CoV-2 infections. This study describes and compares two methods for predicting near-term SARS-CoV-2 incidence in West Virginia counties. The first method, Rt Only, is solely based on producing forecasts for each county using the daily instantaneous reproductive numbers, Rt. The second method, ML+Rt, is a machine learning approach that uses a Long Short-Term Memory network to predict the near-term number of cases for each county using epidemiological statistics such as Rt, county population information, and time series trends including information on major holidays, as well as leveraging statewide COVID-19 trends across counties and county population size. Both approaches used daily county-level SARS-CoV-2 incidence data provided by the West Virginia Department Health and Human Resources beginning April 2020. The methods are compared on the accuracy of near-term SARS-CoV-2 increases predictions by county over 17 weeks from January 1, 2021- April 30, 2021. Both methods performed well (correlation between forecasted number of cases and the actual number of cases week over week is 0.872 for the ML+Rt method and 0.867 for the Rt Only method) but differ in performance at various time points. Over the 17-week assessment period, the ML+Rt method outperforms the Rt Only method in identifying larger spikes. Results show that both methods perform adequately in both rural and non-rural predictions. Finally, a detailed discussion on practical issues regarding implementing forecasting models for public health action based on Rt is provided, and the potential for further development of machine learning methods that are enhanced by Rt.

Call to action: how can the US Ending the HIV Epidemic initiative succeed?

With more than 1·2 million people living with HIV in the USA, a complex epidemic across the large and diverse country, and a fragmented health-care system marked by widening health disparities, the US HIV epidemic requires sustained scientific and public health attention. The epidemic has been stubbornly persistent; high incidence densities have been sustained over decades and the epidemic is increasingly concentrated among racial, ethnic, and sexual and gender minority communities. This fact remains true despite extraordinary scientific advances in prevention, treatment, and care-advances that have been led, to a substantial degree, by US-supported science and researchers. In this watershed year of 2021 and in the face of the COVID-19 pandemic, it is clear that the USA will not meet the stated goals of the National HIV/AIDS Strategy, particularly those goals relating to reductions in new infections, decreases in morbidity, and reductions in HIV stigma. The six papers in the Lancet Series on HIV in the USA have each examined the underlying causes of these challenges and laid out paths forward for an invigorated, sustained, and more equitable response to the US HIV epidemic than has been seen to date. The sciences of HIV surveillance, prevention, treatment, and implementation all suggest that the visionary goals of the Ending the HIV Epidemic initiative in the USA might be achievable. However, fundamental barriers and challenges need to be addressed and the research effort sustained if we are to succeed.